New mechanism found to weaken pseudomonas aeruginosa virulence

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The opportunistic bacterial pathogen Pseudomonas aeruginosa is harmful on account of its resistance to a number of antibiotics. A analysis group from Heinrich Heine University Düsseldorf (HHU) and Jülich Research Center (Forschungszentrum Jülich – FZJ) has now discovered a mechanism that makes it potential to weaken the virulence of the pathogen. Based on this data, a brand new method for antibiotics will be developed, because the authors clarify within the scientific journal JACS Au. The editors of the journal have devoted a canopy story to this discovery.

The bacterium Pseudomonas aeruginosa typically causes a so-called “nosocomial an infection” in people. It is due to this fact one of many harmful hospital micro organism that’s immune to a number of antibiotics. Immunocompromised sufferers are notably affected. The World Health Organisation (WHO) has positioned P. aeruginosa on the checklist of “precedence pathogens” on which analysis efforts ought to focus to seek out new remedy choices.

The bacterium has a broad spectrum of disease-causing virulence elements. These embrace the “kind A phospholipases” (PLA1): Enzymes that may injury the membrane of the host cell and in addition disrupt numerous signaling networks within the contaminated cells. Preliminary work (DOI: 10.7554/eLife.72824) has proven that the enzyme PlaF from P. aeruginosa is a PLA1 that additionally alters the membrane profile and thus contributes to the virulence of the bacterium.

The analysis teams of Professor Dr Holger Gohlke (HHU Institute of Pharmaceutical and Medicinal Chemistry and IBG-4: Bioinformatics at FZJ) and Professor Dr Karl-Erich Jaeger (HHU Institute of Molecular Enzyme Technology at FZJ) have now recognized molecular mechanisms during which medium-chain free fatty acids regulate the exercise of PlaF.

The researchers carried out molecular simulations in addition to laboratory research and in vivo assays. All of those analysis approaches confirmed an oblique impact of the fatty acids on the situation of PlaF within the bacterial membrane in addition to a direct impact by blocking the lively middle of the enzyme. In each methods, the exercise of PlaF is decreased.

On the one hand, the outcomes present proof that the interaction of mechanisms is a regulatory issue for PlaF perform. Professor Gohlke: “We have been solely capable of unravel these advanced relationships by the interplay of computer-aided and experimental strategies throughout the framework of the initiatives funded by the CRC 1208.”

On the opposite hand, the outcomes contribute to understanding the regulatory position of fatty acids. It could also be potential to switch the outcomes to different membrane proteins which have an analogous construction to PlaF.

Finally, in addition they open up new views on how PlaF will be inhibited.

This is a promising method for creating new antibiotics towards P. aeruginosa. These are urgently wanted to fight the damaging pathogens in hospitals.”


Professor Dr Karl-Erich Jaeger, HHU Institute of Molecular Enzyme Technology at FZJ

CRC 1208

The Collaborative Research Centre (CRC) 1208 “Identity and Dynamics of Membrane Systems – From Molecules to Cellular Functions” considers membranes as one of the crucial essential structural entities of organic cells. Membranes are the positioning of many elementary organic processes: They management the transport of gear out and in of the cell and symbolize the primary barrier towards pathogens.

The Collaborative Research Centre is headed by HHU and includes institutes from the Faculty of Mathematics and Natural Sciences and the Medical Faculty on the University, together with Jülich Research Center.

Source:

Journal reference:

Gentile, R., et al. (2024). Molecular Mechanisms Underlying Medium-Chain Free Fatty Acid-Regulated Activity of the Phospholipase PlaF from Pseudomonas aeruginosaJACS Au. doi.org/10.1021/jacsau.3c00725.

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